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Review
, 91 (9)

Viral Epitranscriptomics

Affiliations
Review

Viral Epitranscriptomics

Edward M Kennedy et al. J Virol.

Abstract

Although it has been known for over 40 years that eukaryotic mRNAs bear internal base modifications, it is only in the last 5 years that the importance of these modifications has begun to come into focus. The most common mRNA modification, the addition of a methyl group to the N6 position of adenosine (m6A), has been shown to affect splicing, translation, and stability, and m6A is also essential for embryonic development in organisms ranging from plants to mice. While all viral transcripts examined so far have been found to be extensively m6A modified, the role, if any, of m6A in regulating viral gene expression and replication was previously unknown. However, recent data generated using HIV-1 as a model system strongly suggest that sites of m6A addition not only are evolutionarily conserved but also enhance virus replication. It is therefore likely that the field of viral epitranscriptomics, which can be defined as the study of functionally relevant posttranscriptional modifications of viral RNA transcripts that do not change the nucleotide sequence of that RNA, is poised for a major expansion in scientific interest and may well fundamentally change our understanding of how viral replication is regulated.

Keywords: HIV-1; N6-methyladenosine; Posttranscriptional gene regulation; RNA modification; mRNA function; mRNA stability.

Figures

FIG 1
FIG 1
Overview of m6A addition to RNA transcripts. m6A addition to cellular mRNAs and to the majority of viral mRNAs occurs in the nucleus and is thought to be cotranscriptional. m6A addition is mediated by a complex consisting of METTL3 and several cofactors, including METTL14 and WTAP, which use SAM as a methyl donor. SAM is derived from SAC hydrolase (SAH) and this enzymatic step can be blocked by the drug DAA, resulting in a global inhibition of m6A addition. m6A can also be removed by the predominantly nuclear m6A demethylase ALKBH5, and can be detected in the nucleus by the m6A readers YTHDC1 and YTHDC2, which can modulate RNA. After nuclear export, m6A marks are bound by the cytoplasmic YTHDF1, YTHDF2, and/or YTHDF3 protein, which can regulate mRNA translation and/or stability. While m6A addition primarily occurs in the nucleus, METTL3 and other components of the m6A “writer” complex have been detected in the cytoplasm, possibly in response to stress; cytoplasmic RNA viruses also bear m6A marks.
FIG 2
FIG 2
Subcellular locations of the m6A writers and readers. 293T cells were transfected with plasmids expressing FLAG-tagged versions of the m6A reader proteins YTHDF1, YTHDF2, and YTHDF3 (upper panels) and of the writer components METTL3, METTL14, and WTAP (lower panels), and were then subjected to immunofluorescence using an anti-FLAG antibody. These panels, which are intentionally slightly overexposed, reveal that the m6A writers are all tightly nuclear at steady state while the YTHDF readers are all cytoplasmic. Nevertheless, this result does not preclude the nucleocytoplasmic shuttling of any of these proteins, and the writers, in particular, have been proposed to enter the cytoplasm, possibly in response to stress.

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